This study investigates the relationship between ZFHX3 variants and epilepsy. Whole-exome sequencing was performed on 378 patients with partial epilepsy, and a Drosophila Zfh2 knockdown model was used to validate the association. Compound heterozygous ZFHX3 variants were identified in eight unrelated cases, with a significantly higher burden of variants in the case cohort. In Drosophila, Zfh2 knockdown increased seizure-like behavior and neuronal firing. All patients achieved seizure-free status after antiepileptic drug treatment, including three with neurodevelopmental abnormalities diagnosed as developmental epileptic encephalopathy (DEE). Temporal expression analysis showed that ZFHX3 orthologues were highly expressed in the embryonic stage and decreased dramatically after birth. The study concludes that ZFHX3 is a novel causative gene for childhood partial epilepsy and DEE, with potential implications for precise treatment and understanding the evolutionary course of the illness.This study investigates the relationship between ZFHX3 variants and epilepsy. Whole-exome sequencing was performed on 378 patients with partial epilepsy, and a Drosophila Zfh2 knockdown model was used to validate the association. Compound heterozygous ZFHX3 variants were identified in eight unrelated cases, with a significantly higher burden of variants in the case cohort. In Drosophila, Zfh2 knockdown increased seizure-like behavior and neuronal firing. All patients achieved seizure-free status after antiepileptic drug treatment, including three with neurodevelopmental abnormalities diagnosed as developmental epileptic encephalopathy (DEE). Temporal expression analysis showed that ZFHX3 orthologues were highly expressed in the embryonic stage and decreased dramatically after birth. The study concludes that ZFHX3 is a novel causative gene for childhood partial epilepsy and DEE, with potential implications for precise treatment and understanding the evolutionary course of the illness.